1. Field of the Invention
The present invention relates to a preparation process for biphenylcarboxylic acid amide derivatives or salts thereof which have inhibitory activity against IgE antibody production and are, therefore, useful as a preventive or remedy for allergic immunological diseases.
2. Description of the Background
IgE antibody, which is a kind of immunoglobulin (Ig), is an allergen-specific molecule produced by an IgE antibody producing cell, which has been differentiated from a B cell, triggered by contact of an immunocyte with an allergen in vivo.
IgE antibody is produced in a target organ of an allergy and binds to a receptor on the surface of a mast cell, which is an important effector cell in an allergic reaction, or a basophil (sensitization). After sensitization, allergic chemical mediators such as histamine, leukotrienes, prostaglandins and PAF, and injuring enzymes such as tryptase are released from the mast cell, stimulated by an allergen which has invaded in the living body and reacted with the specific IgE antibody. Then, immediate allergic reactions such as increased vascular permeability, smooth muscle contraction and vasodilation are elicited. From the stimulated mast cell, cytokines such as IL-4, which directly activate other immune system cells, are also secreted. As a result, eosinophils, basophils and the like infiltrate into the tissue, and the allergic chemical mediators and tissue injuring proteins such as MBP, which are secreted by these inflammatory cells, induce a late-phase allergic reaction, thereby lingering the allergic symptom and making them serious.
From this, IgE antibody is considered a substance fundamentally taking part in allergic immunological diseases. A number of IgE antibody production inhibitors have been studied with a view to developing an antiallergic agent.
From such a viewpoint, the present inventors found that compounds having a diamide structure with aromatic rings at both ends of the molecule, particularly, 1,3-bis[4-[4-[(substituted)phenyl]benzoyl]-1-piperazinyl]propane which is a biphenylcarboxylic acid amide derivative represented by the following formula (1): 
wherein, R1, R2 and R3 each independently represents a hydrogen atom or a substituent) has excellent inhibitory activity against IgE antibody production and is useful as an anti-allergic, as described in international patent WO 99/42446.
The preparation process for the biphenylcarboxylic acid amide derivatives however comprises 6 steps as shown in the synthesis route described below. Thus, this route requires a large number of steps. 
For forming a biphenylcarboxylic acid portion of the compound, a cross-coupling reaction (Suzuki reaction) using a (substituted)phenylboronic acid (3a) in the presence of a palladium catalyst is employed. The necessity of carrying out this reaction in the first step leads to an increase in the amount of expensive boronic acid (3a).
It is an object of the present invention to provide a process for preparing a biphenylcarboxylic acid amide derivative represented by the formula (1) or salt thereof conveniently by a reduced number of steps, at lower cost and in high yield.
With a view to developing a novel preparation process of a biphenylcarboxylic acid amide derivative represented by the formula (1) or salt thereof, the present inventors have carried out an extensive investigation. As a result, it has been found that the biphenylcarboxylic acid amide derivative represented by the formula (1) or salt thereof can be prepared by fewer steps in a high yield by reacting, in the presence of a metal catalyst, 1,3-bis[4-(4-halogenobenzoyl)-1-piperazinyl]propane, which is available from N-(4-halogenobenzoyl)piperazine and 1,3-di(leaving group)propane, with a (substituted)phenyl compound having a leaving group containing an element such as boron, thereby forming the biphenylcarboxylic acid portion of the compound in the final step, leading to the completion of the invention.
The present invention is represented by the following reaction scheme: 
wherein X represents a halogen atom, Y represents an leaving group having an element selected from the group consisting of boron, silicon, zinc, tin and magnesium, and R1, R2 and R3 each independently represents a hydrogen atom or a substituent.
In the present invention, there is thus provided a process for preparing a biphenylcarboxylic acid amide derivative represented by the formula (1) by reacting a halogenobenzoic acid derivative represented by the formula (2) with a compound represented by the formula (3) in the presence of a metal catalyst; or salt thereof.
Accordingly, the present invention provides a process for preparing a biphenylcarboxylic acid amide derivative represented by formula (1) or a salt thereof: 
wherein
R1, R2 and R3 each, independently, represent a hydrogen atom or a substituent selected from the group consisting of a hydroxyl group, halogen atoms, lower alkyl groups which may be substituted by 1 to 3 halogen atoms, lower alkoxy groups, amino group, mono(lower alkyl)amino groups, di(lower alkyl)amino groups, lower alkylthio groups, lower alkanoyl groups, and a formyl group,
which comprises reacting, in the presence of a metal catalyst, a halogenobenzoic acid derivative represented by formula (2): 
wherein
X represents a halogen atom,
with a compound represented by formula (3): 
wherein
R1, R2 and R3 have the same meanings as defined above, and
Y represents a leaving group having an element selected from the group consisting of boron, silicon, zinc, tin, and magnesium.
A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following description.
In the present invention, it is preferred that the halogenobenzoic acid derivative (2) is prepared by reacting a compound represented by the formula (4) with a 1,3-di(leaving group)propane.
As each of R1, R2 and R3 in the formulas (1) and (3), examples include hydrogen atom, hydroxyl group, halogen atoms, lower alkyl groups which may be substituted by 1 to 3 halogen atoms, lower alkoxy groups, amino group, mono(lower alkyl)amino groups, di(lower alkyl)amino groups, lower alkylthio groups, lower alkanoyl groups and formyl groups. Of these, preferred are hydrogen atom, lower alkyl groups which may be substituted by 1 to 3 halogen atoms, lower alkoxy groups, di(lower alkylamino) groups, lower alkylthio groups and lower alkanoyl groups, with lower alkoxy, lower alkanoyl and lower alkylthio groups being more preferred. A protecting group may be introduced as needed and after reaction, it may be removed. The term xe2x80x9clowerxe2x80x9d as used herein means that the group has 1 to 6 carbon atoms. This range includes all specific values.
As the lower alkyl groups, preferred are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl and t-butyl groups, of which methyl, ethyl, n-propyl and isopropyl groups are especially preferred.
Examples of the lower alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy and t-butoxy, with methoxy, ethoxy, n-propoxy and isopropoxy groups being preferred.
Examples of the lower alkanoyl groups include acetyl, propionyl, butyryl and isobutyryl groups, with acetyl and propionyl groups being preferred.
Examples of the lower alkylthio groups include methylthio, ethylthio, n-propylthio and isopropylthio groups.
Examples of the mono(lower alkyl)amino groups include methylamino, ethylamino, n-propylamino, and isopropylamino groups.
Examples of the di(lower alkyl)amino groups include dimethylamino, diethylamino, di(n-propyl)amino, and diisopropylamino groups.
Examples of the lower alkyl groups substituted by 1 to 3 halogen atoms include chloroethyl and trifluoromethyl.
Examples of the halogen atoms include chlorine, bromine, iodine and fluorine, with chlorine, bromine and fluorine being preferred.
As each of R1, R2 and R3, especially preferred are C1-6 alkoxy groups, C2-6 alkanoyl groups and C1-6 alkylthio groups.
It is preferred that R1 and R3 each represents a lower alkoxy group and R2 represents a lower alkoxy, lower alkylthio or lower alkanoyl group.
R1, R2 and R3 may be substituted at any position on the benzene ring, but they are preferably substituted at the 3-, 4- or 5-position respectively on the benzene ring. Described specifically, it is preferred that groups selected from C1-6 alkoxy groups, C2-6 alkanoyl groups and C1-6 alkylthio groups are substituted at the 3-, 4- and 5-positions on the benzene ring.
There is no particular limitation imposed on the salt of a biphenylcarboxylic acid amide derivative (1) insofar as it is pharmaceutically acceptable. Examples of the salt include inorganic acid salts such as hydrochlorides, sulfates and nitrates and organic acid salts such as methanesulfonates, acetates, oxalates and citrates.
Preferred examples of the biphenylcarboxylic acid amide derivative (1) or salt thereof include 1,3-bis[4-[4-(3,4,5-trimethoxyphenyl)benzoyl]-1-piperazinyl]propane dihydrochloride, 1,3-bis[4-[4-(4-isopropoxy-3,5-dimethoxyphenyl)benzoyl]-1-piperazinyl]propane dimethanesulfonate, 1,3-bis[4-[4-(3,5-dimethoxy-4-methylthiophenyl)benzoyl]-1-piperazinyl]propane dihydrochloride, 1,3-bis[4-[4-(4-ethoxy-3,5-dimethoxyphenyl)benzoyl]-1-piperazinyl]propane dimethanesulfonate, 1,3-bis[4-[4-(4-acetyl-3,5-dimethoxyphenyl)benzoyl]-1-piperazinyl]propane dihydrochloride, and 1,3-bis[4-[4-(3,5-dimethoxy-4-propoxyphenyl) benzoyl]-1-piperazinyl]propane dihydrochloride.
The compound of the formula (4) which is a raw material compound of the invention process is available, for example, by reacting a 4-halogenobenzoyl chloride with piperazine in the presence of concentrated hydrochloric acid in accordance with the description in J. Med. Chem., 30, 49-57(1987), incorporated herein by reference.
Per mole of the 4-halogenobenzoyl chloride, piperazine is used in an amount of 2 mole equivalents and concentrated hydrochloric acid is used in an amount of 2 mole equivalents. As the halogen atom represented by X in the formula (4), bromine is especially preferred.
The halogenobenzoic acid derivative (2) is available by condensation of the compound of the formula (4) and 1,3-di(leaving group)propane.
Examples of the 1,3-di(leaving group)propane include 1,3-dihalogenopropanes and compounds having equivalent reactivity with 1,3-dihalogenopropanes, such as bis(alkylsulfonyloxy)propanes. Of these, 1,3-dibromopropane is especially preferred.
The condensation reaction may be effected, if necessary, in a solvent such as methanol, ethanol, toluene, xylene, methylene chloride, dimethylformamide or dimethylsulfoxide, and if necessary, in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydride or butyl lithium, or an organic base such as 1,8-diazabicyclo[4.3.0]undec-7-ene, pyridine or triethylamine. The reaction time and reaction temperature fall within ranges of 5 minutes to 100 hours and xe2x88x9220 to 100xc2x0 C., respectively. They vary depending on the combination of the above-described raw materials. Particularly preferred is reaction of a halogenobenzoic acid derivative (2) with 1,3-dibromopropane in dimethylformamide in the presence of sodium carbonate as a base at 60 to 100xc2x0 C. for 5 to 10 hours.
Coupling reaction of a halogenobenzoic acid derivative (2) with a compound of the formula (3) is conducted in a solvent in the presence of a metal catalyst (Metal-catalyzed Cross-coupling Reactions: Diederich, F.; Stang, P. J., Eds., Wiley-VHC: Weinheim, 1998, incorporated herein by reference.; Stanforth, S. P., Tetrahedron 1998, 54 263-303, incorporated herein by reference).
Examples of Y in the compound of the formula (3) include dihydroxyboron, (lower alkylenediolato)borons, di(lower alkoxy)borons, di(lower alkyl)borons, dihalogeno(lower alkyl)borons, dihalogeno(lower alkyl)silicons, halogenozincs, tri(lower alkyl)tins and halogenomagnesiums. Examples of the above-described lower alkylene group include C2-6 alkylene groups. Of these, ethylene, propylene and tetramethylethylene groups are preferred. Examples of the lower alkoxy group include C1-6 alkoxy groups, of which methoxy, ethoxy, n-propoxy and isopropoxy groups are preferred. Examples of the lower alkyl group include C1-6 alkyl groups, of which methyl, ethyl, n-propyl and isopropyl groups are preferred. Examples of the halogen atom include fluorine, chlorine, bromine and iodine.
Dihydroxyboron and (pinacolato)boron are especially preferred as Y. (Miyaura, N; A. Suzuki, A. Chem. Rev. 1995, 95, 2457-2483, incorporated herein by reference).
The compound of the formula (3) can also be prepared from a corresponding halide or sulfonate (xe2x80x94OSO2CqF2q+1 (q stands for 0 to 4)) in a reaction system (Miyaura, N. et al. Tetrahedron Lett. 1997, 38, 3447-3450, incorporated herein by reference; Giroux, A. et al. Tetrahedron Lett. 1997, 38, 3841-3844, incorporated herein by reference; Masuda, Y. et al. Org. Chem. 2000, 65, 164-168, incorporated herein by reference). Examples of the halogen of the halide include chlorine, bromine and iodine.
As the metal catalyst, preferred are palladium compounds such as tetrakis(triphenylphosphine)palladium(O), tris(bisbenzylideneacetone)dipalladium(O), palladium(II) acetate, palladium(II) chloride, dichlorobis(triphenylphosphine)palladium(II), dichloro[1,2-bis(diphenylphosphino)ethane]palladium(II), dichloro[1,4-bis(diphenylphosphino)butane]palladium(II), and dichloro[1,1xe2x80x2-bis(diphenylphosphino)ferrocene]palladium(II) and nickel compounds such as tetrakis(triphenylphosphine) nickel (O) and bis(acetylacetonato)nickel(II).
When Y of the formula (3) is a boron-containing leaving group, use of a palladium compound is particularly preferred.
As the solvent, use of benzene, toluene, xylene, diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, acetonitrile, dimethylformamide, N-methylpiperidone, methanol, ethanol or water is preferred,
It is preferred to add a ligand and a base if necessary. Examples of the ligand include tri-butylphosphine, triphenylphosphine, tri(o-tolyl)phosphine, tri(2-furyl)phosphine, 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane and 1,1xe2x80x2-bis(diphenylphosphino)ferrocene, while examples of the base include sodium acetate, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, cesium fluoride, tetxabutylammonium fluoride and triethylamine.
Reaction temperature and reaction time are 0 to 150xc2x0 C. and 0.5 to 100 hours, respectively. When the leaving group of the compound of the formula (3) has boron and a palladium compound is used as a metal catalyst, reaction conditions at 0 to 80xc2x0 C. for 2 to 15 hours are preferably employed.
The target compound can be isolated or purified from the reaction mixture, for example, by filtration, extraction, drying, concentration, recrystallization or various chromatographies.
The biphenylcarboxylic acid amide derivative (1) thus prepared can be converted into its acid addition salt in a conventional manner.